NEW ORLEANSHairy cell leukemia (HCL) has the highest reported
surface expression of CD20 of leukemias studied to date, according to
research reviewed at the ASH meeting. In a symposium presentation,
Deborah A. Thomas, MD, and colleagues from the M.D. Anderson Cancer
Center in Houston, reported that the anti-CD20 monoclonal antibody
rituximab (Rituxan) is active against HCL. Response appears to
correlate with a decrease in serum interleukin-2 (IL-2) receptor
levels. In a poster presentation, Robert J. Kreitman, MD, and
colleagues from the National Cancer Institute reported that
recombinant immunotoxins containing truncated Pseudomonas exotoxin
and targeting either CD25 or CD22 can induce some major responses in
patients with refractory HCL.
Rituximab Pilot Study
Currently, chlorodeoxyadenosine (CdA) is widely used in treatment of
HCL, but patients beyond 7 years of follow-up have an increased risk
of relapse, and therapy is accompanied by a high risk of infectious
complications. Durable remissions are achieved in most patients, but
up to 25% do not respond either initially or eventually, and many
require chronic blood product support.
Dr. Thomas said that HCL has the highest surface expression of CD20
of any leukemia. Rituximab was an attractive therapeutic candidate
because it is a monoclonal antibody directed at the CD20 antigen. Her
research team enrolled 10 HCL patients in a pilot study of the
antibody. All had prior CdA chemotherapy; two were refractory and
eight had responded but relapsed. Five patients were heavily
pre-treated, with two or more prior therapies.
Patients were treated with rituximab 375 mg/m² IV weekly for 8
weeks. At the time of the ASH meeting, 9 of 10 patients were
evaluable for response, with a median follow-up of two months. Dr.
Thomas reported an overall response rate of 67% (6/9), including a
complete response rate of 33% (3/9) and a complete response with
minimal residual disease in 22% (2/9).
Serum IL-2 Receptors
The researchers studied changes in serum IL-2 receptors, which are
expressed at high levels in HCL. In patients who received all eight
planned doses of rituximab and had complete remissions, serum IL-2
receptor levels returned to undetectable levels. Four patients
received only 4 of the 8 planned doses, and serum IL-2 receptor
levels did not drop to undectable level in these patients.
Toxicity of rituximab was generally mild, with no infections and
mostly only mild fever and chills. One patient had grade 3 myalgia
requiring narcotics after each dose of rituximab but was able to take
all eight planned doses. Rituximab appears promising with
minimal toxicity in relapsed/refractory HCL and warrants further
study, Dr. Thomas concluded. Rituximab may also have a
role in treatment of minimal residual disease.
Targeting CD25 and CD22
Dr. Kreitmans group tested two recombinant immunotoxins
targeting either CD25 (the IL-2 receptor alpha chain) or CD22. LMB-2
is composed of the variable domains of the anti-Tac monoclonal
antibody to CD25, fused to bits of Pseudomonas immunotoxin. BL-22 is
composed of the variable domains of the RFB4 monoclonal antibody to
CD22, fused to the same Pseudomonas toxin. In this Phase I study,
four patients were treated with LMB-2, and seven were treated with BL-22.
Toxicities included reversible transaminase elevations, fever, and
hypoalbuminemia. Dr. Kreitman said that BL-22 toxicity has been
blocked by anti-inflammatory agents, and similar toxicity prevention
is planned for LMB-2. Toxicity appears to be related to a
systemic inflammatory response syndrome, which may be preventable by
anti-inflammatory agents, he said.
Dr. Kreitman reported that LMB-2 produced complete response (CR) in 1
of 4 patients and partial response (PR) in 3 of 4. BL-22 produced CR
in 3 of 7 patients and PR in 2 of 7 patients. LMB-2 and BL-22
are clinically active in patients with chemotherapy-refractory
hematologic malignancies, particularly HCL, where the response rate
is 100% in patients treated with 10-63 µ/kg QOD x 3 of LMB-2 or
BL-22, Dr. Kreitman concluded. Complete responses appear
durable. BL-22 appears to be clinically active in patients with the
poor-prognosis variant HCL characterized by CD25-/CD22+ malignant cells.